Pan American Society for Clinical Virology Position Statement on FDA Oversight of

Laboratory-Developed Tests (LDTs).

The Pan American Society for Clinical Virology (PASCV) is an international society, with a
membership of approximately 600 professionals. Members of PASCV perform laboratory
testing for the detection, quantification, and characterization of viral pathogens. Much of this
testing involves the use of molecular-based assays that have been fully developed and validated
by individual testing laboratories. Many of our members are also involved with the development
and performance of molecular testing for bacterial, mycobacterial, parasitic, and fungal
pathogens. Our membership includes physicians, doctoral scientists, and medical technologists,
representing academic medicine, clinical laboratories, commercial laboratories, the
pharmaceutical industry, and the in vitro diagnostics industry. We thank the organizers for the
opportunity to comment on the oversight of laboratory-developed tests (LDTs).

When considering how best to regulate LDTs several important issues need to be considered.

Molecular testing has revolutionized the practice of infectious diseases and clinical virologists
have been pioneers in the application of molecular techniques to clinical diagnostics. In large
part, the development and implementation of LDTs for viral diagnosis and monitoring has grown
out of necessity as the availability of FDA-cleared commercial tests has been limited over the
years and conventional methods of virus culture and antigen detection are often insensitive with
turnaround times that preclude having an impact on clinical care. As such we have been
developing, validating, and performing qualitative and quantitative molecular testing in clinical
laboratories since the mid 1990’s. Molecular testing is the standard of care for detection and
quantification of many pathogens, for which there is no FDA cleared/approved test available.
Examples of disease states for which IVD diagnostic-tests are not available include central
nervous system infections due to herpes simplex virus and varicella zoster virus and for
monitoring cytomegalovirus, BK virus, adenovirus, and Epstein Barr virus levels in transplant
recipients. In short, laboratory-developed molecular tests are now essential for the practice of
infectious diseases.

The ability to quickly implement LDTs for various pathogens and to use a single platform and
common protocols when appropriate, is cost effective, increases throughput, greatly reduces
turnaround and thus enhances clinical impact and provides a critical service to our patients,
healthcare providers, and to our infection control teams. Many laboratories fully rely on LDTs
to rapidly develop tests for emerging pathogens, as was clearly evident during the recent 2009
H1N1 influenza A pandemic. The availability of testing protocols developed by the CDC and
sequence information made public through the NIH genetic database, allowed for many clinical
laboratories to quickly validate and implement molecular testing for this important public health
pathogen. The result was highly accurate molecular testing provided in a very timely manner in
order to have the greatest impact on clinical decision making and patient care. There is little
doubt that new pathogens and microbial resistance to therapeutic drugs will continue to emerge,
requiring a rapid and effective response by clinical laboratories.

Clinical laboratories have never been under greater cost constraints than they are today. A
regulatory process for LDTs that is overly burdensome and expensive will limit access to testing
and negatively impact clinical care. Large tertiary care centers with critically ill, often
immunocompromised patients are highly dependent on LDTs.

When a molecular test is eventually commercialized and FDA-cleared, it often comes at a

substantially higher cost than LDTs and many PASCV members have noted that the performance
of these tests do not always meet or exceed that of their LDT counterparts. Therefore, even
when FDA cleared tests are made available, clinical laboratories must still have the flexibility to
continue offering LDTs.

If the process implemented to regulate LDTs is expensive, time consuming, and labor-involved,
it will clearly have an adverse impact on most hospital-based laboratories. Hospital-based
laboratories may be forced to refer their testing to off-site reference laboratories that may have
greater resources and capabilities to absorb the process and its associated costs. This would
result in increased cost and would have a negative impact on turnaround times for reporting tests
results.

Moreover, as key components of educational programs for laboratory and clinical trainees, the
development, quality assurance, and interpretation of LDTs are fertile ground for the
advancement of diagnostics.
Finally, since testing is almost entirely on-site, substantial physician feedback about quality and
impact of testing are readily available, allowing laboratories to modify and improve testing as
necessary.

With that said, many laboratories would certainly welcome high quality FDA cleared
commercial tests if they are reasonably priced, user friendly, and can efficiently detect multiple
analytes on a single platform. The development, validation, quality control, and continuous
monitoring of LDTs are arduous tasks and clinical laboratories would prefer not to manufacture
their own assays. However, until acceptable FDA-cleared commercial tests are made readily
available, LDTs will remain essential for high quality, cost-effective patient care.

With this as background we respectively provide the following suggestions:

• The FDA should work with CLIA to bring consistency to the current regulatory process;
this can be done in partnership with CLSI and CAP. For example, the CAP checklist for
molecular microbiology has been completely revised to include a section specific for
LDTs. By working with CAP and CLSI it should be possible to establish practical
guidelines for assay verification and validation that can be applied to all CLIA-certified
laboratories without the need for an additional regulatory process. This could include
well-defined standards for the analytical and clinical validation processes (e.g., providing
clear guidelines for assessing performance, limit of detection and quantification, and
reproducibility, as well as the number of positive and negative specimens required to be
examined). Provisions should be made for rare infections such as encephalitis due to
herpes simplex virus.

• Clear and realistic guidelines for validation should be set for laboratories that use
alternative specimens types in FDA cleared tests, for example rectal swabs for detection
of Chlamydia trachomatis. Specific guidance should be provided to laboratories that
modify FDA cleared tests, for example with an alternative extraction method. This
ability to modify extraction or use alternative but comparable real-time instrumentation is
very important for laboratories, as purchasing a wide array of instruments and/or systems
is not realistic or possible.

• With the risk stratification approach proposed by the FDA, the impact of an incorrect
result needs to be balanced with the consequences of not having the test available and
 potentially using inferior testing methods instead (e.g., culture- or antigen-based tests), or
having results delayed such that they no longer impact clinical care.

• When considering how to regulate LDTs, we suggest that the FDA carefully assess the
resources needed for the process to avoid delays in approval, as this could limit access to
testing. It may be helpful for the FDA to communicate with laboratory directors in NY
State to obtain a perspective on the outcome of the extensive regulatory process that is
required for LDTs and how the time for approval impacts access to testing.

• We encourage the FDA to work with members of professional societies, such as those
represented at this meeting (e.g., ASM, PASCV, AMP), in establishing these guidelines.
This represents a pool of highly knowledgeable and technically skilled individuals who
can offer a real world perspective.

• Finally we ask the FDA to work with professional organizations to establish and fund a
specimen repository that could be used by laboratories for test validations, with particular
focus on rare pathogens. The repository could also be used by commercial companies
willing to submit a test to the FDA. Establishing and maintaining a repository would
require resources for organization and oversight, but could assist in ensuring uniform
quality of LDTs.

As we move forward with this process, it is essential that we are very mindful of unintended
consequences. Actions that create a burdensome regulatory process, slow turnaround time,
increase costs, or limit access to testing will have a significantly negative impact on the quality
of patient care.

On behalf of PASCV, thank you for the opportunity to comment.

Angela M Caliendo, MD, PhD

President, PASCV
404-712-5721
acalien@emory.edu